There will be an estimated 585,720 deaths due to cancer in the United States this year resulting from tumors that regrow after therapy. Most patients suffering from cancer respond initially to treatment resulting in shrinking tumors. In some cases, tumors are completely eliminated or tumor shrinkage is maintained resulting in an effective cure for the patient. However, many tumors will eventually switch from shrinkage to regrowth resulting in tumors that are resistant to therapy. The initial response to treatment results from successful killing of bulk tumor cells, but a subset of tumor cells, the cancer stem cells (CSC), are not sensitive to current therapies. In fact, treatment often causes the expansion of CSC populations through TGF? signaling. The expansion of surviving CSC seeds the regrowth of tumors that are resistant to therapy. Identifying new therapies that inhibit CSC expansion would prevent the regrowth of resistant tumors significantly improving the number of effective cures following cancer treatment. An innovative model was used to identify factors that could inhibit the expansion of CSC driven by TGF? signaling following treatment. IFN?, an important factor in immune system responses, was shown to prevent the expansion of CSC driven by TGF?. Therefore, we hypothesize that IFN? inhibits TGF? signaling and will prevent the regrowth of resistant tumors following treatment. Two aims have been developed to test this hypothesis. Aim 1 will determine: (1) how IFN? suppresses TGF? signaling; and (2) which components of IFN? signaling are required to suppress the TGF? signaling. Aim 2 will determine: (1) the optimal dosing for IFN? to inhibit tumor regrowth; (2) the direct effects of IF? that inhibit tumor regrowth; and (3) the effect of IFN? on the immune system that inhibits tumor regrowth. IFN? has been used alone to treat cancer, because at high doses it inhibits tumor growth. Unfortunately, IFN? use in humans is limited by side effects at the high doses required to treat tumors. Our data suggests that IFN? may prevent tumor regrowth at much lower doses. Therefore, we suggest using lower doses of IFN? in combination with current therapies to inhibit tumor regrowth. Our short-term goal is to demonstrate that adding IFN? to current treatments for cancer will result in less regrowth of treated tumors in mouse models. Our long-term goal would be to use IFN? as a combination therapy in human cancers to prevent tumor regrowth and reduce patient death. Since IFN? is already used in humans, it will be easier to have it tested as a combination therapy at lower doses. Successful completion of this proposal would provide a new treatment to prevent the regrowth of therapy-resistant tumors that cause the majority of patient deaths due to cancer.